System for quantifying blood flow in tissue with periodic updating of tissue baseline conditions

ABSTRACT

Disclosed are methods and apparatus for determining blood flow in tissue. Particularly methods and apparatus are disclosed for establishing baseline thermal properties for the tissue and providing one or more steps for periodically determining changes in the tissue thermal properties that correspond to a need for a new baseline and establishing the new baseline.

DOMESTIC PRIORITY CLAIM

[0001] This application claims priority from two commonly owned,copending United States Provisional Applications—Serial No. 60/403,496,filed Aug. 14, 2002, and Serial No. 60/370,483, filed Apr. 5, 2002, thedisclosures of which are hereby incorporated herein by reference.

SUMMARY OF THE INVENTION

[0002] The present invention covers technology developed to provideclinicians with a powerful prognostic tool for quantifying tissue bloodflow (i.e., “perfusion”) in continuous, real-time. The measurements madeby the apparatus of the present invention have long been sought afterand represent important parameters in the understanding and managementof many critical medical situations, and prior to the development ofthis technology, the practical capability to get continuous, real-time,soft tissue perfusion measurements in absolute units, did not exist. Thehigh clinical value of the technology behind this invention has beendocumented in life-saving neurosurgical and organ transplantationsurgery cases, among others.

[0003] In the monitoring of perfusion in the tissue of a subject (i.e.:the flow of blood in a capillary bed) it is useful to have a continuousor nearly continuous stream of data over time. The accuracy ofmeasurements is affected by various physiologic and instrument baselinechanges. Thus, it is also useful to monitor baseline conditions andadjust for baseline shifts over time. The monitoring system surveysselected baseline factors that may adversely affect the integrity of themonitored data and uses the results to make corrections.

[0004] The continuous measurement of perfusion over time is valuable inmany clinical settings. Among them are the measurement of perfusion inthe brain of patients with traumatic brain injury to anticipate adverseconditions such as cerebral ischemia, the monitoring of perfusion inorgan transplantation to assess isehemia caused by thrombotic andreperfusion injury and the monitoring of perfusion in flaps inreconstructive plastic surgery to assess tissue viability. The perfusionvalue is also an indicator of the presence or absence of shock andmonitoring perfusion over time may permit the clinician to anticipateand treat shock.

[0005] Approximately 370,000 Americans suffer traumatic head injuryannually. By using the apparatus of the present invention to measurecontinuous, real-time cerebral tissue blood flow, clinicians canidentify patients at risk for ischemia due to vasospasm or cerebraledema (brain swelling), and measure the patient's tissue blood flowresponse to therapies implemented to correct the pathology. In addition,other critical neurosurgical interventions, such as aneurysm repair,tumor and arterial-veinous malfunction removal and procedures to relievepatients suffering from subarachnoid hemorrhage are among those thatwill also benefit from the valuable prognostic data provided by theapparatus of the present invention.

[0006] One embodiment, the Bowman Perfusion Monitor, Model 500, is adevice that monitors tissue blood flow continuously at the capillarylevel in real-time and in absolute units of ml/100 g-min. The Model 506perfusion-monitoring device utilizes thermal diffusion technologydescribed here through its minimally invasive, QFlow 500 Probe, whichphysicians can implant in cerebral or any other soft tissue.

[0007] The present invention may be used over extended periods of timein living subjects and provide thermal property and perfusion data witha high degree of accuracy. This obtains even when tissue physiology ischanging and the physiological changes are accompanied by changingthermal properties in the tissue. Thermal properties of particularinterest are the properties of diffusivity and conductivity which areuseful in the determination of tissue perfusion.

[0008] To accommodate physiological or non-physiological changes overtime, the present invention provides methods and apparatus fordetermining baseline thermal conditions of the tissue at a selectedlocation or site and for establishing baseline criteria to be used forthe periodic updating of baseline tissue conditions (in situcalibration). The baseline tissue conditions or thermal properties maychange with time. Thus, one or more steps are provided for periodicallydetermining the need for updating to new baseline tissue conditions (insitu recalibration) as tissue conditions change.

[0009] Calibration or the establishing of a baseline may also take intoaccount internal monitoring system parameters (artifacts). Recalibrationor the establishing of a new baseline may include one or more steps forperiodically determining parameter changes and, when changes are outsideof an acceptable range, recognizing the need for new or updated baselinecriteria. Accordingly baseline criteria are updated as the parametersand conditions unintentionally change.

[0010] The process of establishing a new or updated baseline may bemanually initiated or the system may automatically self-adjust (i.e.:self-recalibrate). The instrument may self-adjust automatically andperiodically when physiology changes by some predetermined amount orwhen a combination of physiologic conditions and system parameterschange by a predetermined amount. The system monitors the parameters andconditions to determine when values have changed to be outsidepredetermined limits and recalculates baseline when limits are exceeded.

[0011] One embodiment of the present invention is directed to a methodfor the periodic updating of tissue baseline conditions in order to makeperfusion measurements over extended periods during which tissuebaseline conditions change as a consequence of multiple physiologic andnon-physiologic factors. The method may comprise the following steps:(a) perform in situ calibration of a perfusion sensor in the tissue,that is, establish baseline tissue conditions; (b) make perfusionmeasurement in tissue and (c) automatically recognize conditions underwhich the in situ calibration is no longer valid. Examples of suchconditions include physiologic conditions such as tissue and vasculardamage, tissue edema, tissue scar formation, influence of a largevessel, change in vascular status, such as blood volume, vasodilation,and vasoconstriction; changes in perfusion; changes in blood pressure;changes in tissue pressure; changes in tissue temperature; changes inblood temperature; changes in tissue metabolism; and/or measurement ofartifact conditions, such as sensor motion relative to the tissue,excessive sensor-tissue contact force inducing capillary collapse,insufficient sensor-tissue contact force resulting in artifactualtransduction of perfusion, sensor cross-talk, ambient temperaturechanges, electrical interference, instrumentation drift. Following step(c), (d) automatically perform a recalibration, selected from one ormore of the following to reestablish baseline conditions; proberecalibration and instrumentation recalibration; and (e) repeat thesteps as necessary to maintain optimum operation.

BRIEF DESCRIPTION OF THE DRAWINGS

[0012] Certain preferred embodiments are described below with referenceto the accompanying figures in which:

[0013]FIG. 1 is a front view depiction of an embodiment of theinvention.

[0014]FIG. 2 is a block diagram of an embodiment of a system in whichthe disclosed techniques can be used.

[0015]FIG. 3 is a flow chart of one embodiment of the present invention.

[0016]FIG. 4 is a flow chart of a system to repeatedly recalibratethermal-based perfusion sensors.

[0017]FIG. 5 is a high-level general block diagram of a method fordetermining properties of a medium.

[0018]FIG. 6 is detailed block diagram of a method for determiningproperties of a medium.

[0019]FIG. 7 is a block diagram of an apparatus for determining theproperties of a medium.

[0020]FIG. 8 is a simplified diagram of one embodiment of a circuit usedin a control circuit.

[0021]FIG. 9 is a simplified diagram of one embodiment of anothercircuit used in a control circuit.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0022] This invention can be implemented by use of a system such asshown in FIG. 1 and illustrated schematically in FIG. 2. FIG. 1 showsthe Bowman Perfusion Monitor with a display screen 52, a keyboard 62,connector 53 for a perfusion probe, a slot 63 to permit passage of aprinted tape and an on/off switch 51. As explained in the Bowman patentsreferenced below and illustrated by FIG. 2, a probe 10 is immersed in amedium (e.g.: tissue) 11 and can be heated by a heater voltage V_(h)(t)supplied via control circuit 13. The sensed voltage V_(s)(t) from probe10 is supplied to A/D converter 15 for supplying to a data processor 14in digital form for suitable processing thereof in order to determine k(intrinsic thermal conductivity), α (diffusivity), and ω (flow rate orperfusion), the values of which can be displayed in a display device 16.The values of probe calibration constants k_(b), a, and R_(i) can besupplied via a suitable input unit that may be in the form of a memorychip. Such operation is essentially described in the aforesaid patentsfor a particular mathematical model described therein and the samesystem as generally depicted therein can also be used for a differentmathematical model, the processing equations required to be implementedin data processor 14 being different depending on the mathematical modelselected.

[0023] The method of determining properties of a medium by causing athermal change in the medium and then calculating it's properties basedon the medium's response to the thermal change is described in detail inU.S. Pat. No. 4,059,982 to H.F. Bowman issued on Nov. 29, 1977; U.S.Pat. No. 4,852,027 to H. F. Bowman and W. H. Newman issued on Jul. 25,1989 and U.S. Pat. No. 5,035,514 to William H. Newman issued on Jul. 30,1991, the disclosures of which are hereby incorporated herein byreference.

[0024] As illustrated in FIGS. 3 and 4, methods and software apparatusare provided to repeatedly recalibrate thermal-based perfusion sensorsand related instrumentation. The system monitors the conditions of theelectronic instrument and conditions affecting the sensor and, via thesensor, also monitors the conditions of tissue, organ and the overallphysiology of the subject to establish a baseline. When the weightedcombination of conditions in the instrument and sensor and in thephysiology of the subject fall outside a preset threshold, a perfusionmeasurement less accurate than desired is indicated and the systemdetermines that a new baseline (recalibration) is needed. The system maymonitor these conditions or use inputs from other devices that monitorphysiologic or instrument conditions. The establishment of a newbaseline (recalibration) may be initiated manually after the systemprompts the operator or it may be automatically initiated by the system.Similarly, the system may also be prompted by an external apparatus toautomatically perform part or all of the recalibration process.

[0025] The instrument conditions that are monitored include, but are notlimited to; ambient temperature changes, electrical interference, andinstrumentation drift. The thermal-based perfusion sensor conditionsthat are monitored include, but are not limited to; excessivesensor-tissue contact force that can result in capillary collapse,insufficient sensor-tissue contact force that can result in artifactualthermal transduction, sensor crosstalk, and movement of the sensorrelative to the tissue. The physiologic conditions of the subject thatare monitored include, but are not limited to; tissue and vasculardamage, tissue edema, tissue scar formation, influence of a largevessel, change in vascular status (i.e.: blood volume, vasodilation, andvasoconstriction), changes in perfusion, changes in blood pressure,changes in tissue pressure, changes in tissue temperature, changes inblood temperature, and changes in tissue metabolism.

[0026] According to certain embodiments of the invention a method fordetermining perfusion in living tissue includes the steps of: (1)establishing baseline tissue criteria by determining an unperturbedtemperature of the tissue, causing the temperature of the tissue tochange from a first unperturbed temperature to a second temperaturedifferent from said first temperature for a time period, and determininga value or values for one or more thermal properties of the tissueduring the time period; (2) calculating a perfusion value for the tissueduring the time period using said thermal property value or values, and(3) evaluating one or more physiological and artifactual conditions todetermine if previously established baseline criteria are materiallyaffected by said conditions. If previously established baseline criteriaare materially affected by changed conditions, (4) the first step isrepeated to establish new values for baseline thermal properties. Thethermal properties for which a value or values are determined mayinclude either or both of thermal conductivity and thermal diffusivity.

[0027] Certain embodiments of a method for measuring perfusion in tissuecomprise the steps of: (1) establishing a baseline criteria for tissueconditions, comprising the steps of: (A) determining an unperturbedtemperature of the tissue, (B) causing the temperature of said tissue tochange from a first unperturbed temperature to a second temperaturedifferent from said first temperature during a time period the initialportion of which is affected strongly by conductive factors and a secondportion of which is affected strongly by convective factors, (C)calculating an intrinsic thermal conductivity and a diffusivity of saidtissue during a first selected portion of said time period, (2)obtaining measurements of perfusion of the tissue comprising the stepsof: (A) calculating a perfusion of said tissue at a second selectedportion of said time period using said calculated intrinsic thermalconductivity and diffusivity, (B) re-calculating the intrinsic thermalconductivity and diffusivity of said tissue during said first selectedportion of said time period using said calculated perfusion, (C)re-calculating the perfusion of said tissue at said second selectedportion of said time period using said recalculated intrinsic thermalconductivity and diffusivity, and (D) repeating steps 2(B) and 2(C)until the recalculated intrinsic thermal conductivity and diffusivityand the re-calculated perfusion each converge to a substantiallynon-changing value; (3) determining need for new baseline criteriacomprising evaluating physiological conditions that may affect baselinetemperature, conductivity and/or diffusivity values.

[0028] In certain embodiments step (3) further comprises the step ofevaluating measurement artifact conditions that may affect baselinetemperature, conductivity and/or diffusivity values. Other embodimentsfurther comprise a step (4) when new baseline criteria are indicated bystep (3) for permitting the temperature of the tissue to relax to anunperturbed state and then repeating step (1). In certain otherembodiments step (1)(B) includes: activating said temperature changingmeans when immersed in said tissue to change the temperature of saidtissue. In still other embodiments step (1)(B) includes: immersing acooling means in said tissue; and applying power to said cooling meansto cool said tissue from said first unperturbed temperature. Theintrinsic thermal conductivity and diffusivity of step (1)(C) arecalculated at the first selected portion of said time period whenconvective factors dominate and step (2)(A) is calculated at the secondselected portion of said time period when conductive factors dominate.

[0029] In certain embodiments step (1)(B) includes: applying power tosaid heating means while in contact with said tissue to heat said tissuefrom said first unperturbed temperature to said second temperature. Inother embodiments the heating means has a substantially sphericalconfiguration and is of a type referenced in the previously mentionedU.S. Pat. Nos. 4,059,981 and 5,035,514. Said intrinsic thermalconductivity and diffusivity are calculated and recalculated in steps(1)(C) and (2)(B) and the perfusion is calculated and recalculated insteps (2)(A) and (2)(C) using the following equation: $\begin{matrix}{\quad {{{P(t)} = {\frac{4\pi \quad {ak}_{m}\Delta \quad T}{\frac{1}{5\gamma} + \frac{1}{1 + {\lambda \quad a}}}\left\lbrack {1 + \frac{\frac{a}{\sqrt{\pi \quad a_{m}}}{f(t)}}{\frac{1 - {\lambda^{2}a^{2}}}{5\gamma} + 1 + {\lambda \quad a}}} \right\rbrack}}\quad {{V_{b}(t)} = {\Delta \quad T}}\quad {{P(t)} = 0}}\quad} & (i) \\{\frac{V_{b}(t)}{\Delta \quad T} = {\frac{a/\sqrt{{\pi\alpha}_{m}}}{\frac{1 - {\lambda^{2}a^{2}}}{5\gamma} + 1 - {\lambda \quad a}}\begin{bmatrix}{\left\{ {{f\left( {t - t_{heat}} \right)} - {f(t)}} \right\} +} \\{\frac{a/\sqrt{\pi \quad a_{m}}}{\frac{1 - {\lambda^{2}a^{2}}}{5\gamma} + 1 + {\lambda \quad a}}\frac{\sqrt{t_{heat}}^{{- \lambda}\quad 2{am}^{t}}}{t\sqrt{t - t_{heat}}}}\end{bmatrix}}} & ({ii})\end{matrix}$

[0030] wherein P(t) is the power applied, a is the radius of thespherical heating means, k_(m) and α_(m) are, respectively, theintrinsic thermal conductivity and thermal diffusivity of said tissue, γis the ratio k_(b)/k_(m), k_(b) is the intrinsic thermal conductivity ofthe spherical heating means, λ is equal to {square root}{square rootover (wc_(m)/k_(m))}, where w is perfusion and c_(m) is the specificheat of the perfusate, V_(b) is the bead mean volumetric temperatureduring cooling, ΔT is the volume averaged constant temperature changeduring the heating phase, t_(heat) is the length of time for whichheating is applied and f(t) represents the temporal form of thetransient power applied to said heating means as a function of time.

[0031] Other variations, include but are not limited to, where saidheating means has a substantially spherical configuration and saidintrinsic thermal conductivity and diffusivity are calculated andrecalculated in steps (1)(C) and (2)(B) and the perfusion is calculatedand recalculated in steps (2)(A) and (2)(C) using the followingequation:

P=P_(o)

[0032] and $\begin{matrix}{{{V_{b}(t)} = {\frac{P_{o}}{4\pi \quad {ak}_{a}}\left\lbrack {\frac{1}{5\gamma} + \frac{1}{1 + {\lambda \quad a}} - {\frac{a/\sqrt{\pi \quad \alpha_{m}}}{1 - {\lambda^{2}a^{2}}}{f(t)}}} \right\rbrack}}{P = 0}} & ({iii}) \\{{V_{b}(t)} = {\frac{P_{o}}{4\pi \quad {ak}_{a}\sqrt{\pi \quad \alpha_{m}}}{\frac{1}{1 - {\lambda^{2}a^{2}}}\left\lbrack {{f\left( {t - t_{heat}} \right)} - {f(t)}} \right\rbrack}}} & ({iv})\end{matrix}$

[0033] wherein P_(o) is the constant power applied during the heatingphase, a is the radius of the spherical heating means, k_(m) and α_(m)are, respectively, the intrinsic thermal conductivity and thermaldiffusivity of said tissue, γ is the ratio k_(b)/k_(m), k_(b) is theintrinsic thermal conductivity of the spherical heating means, λ isequal to {square root}{square root over (wc_(m)/k_(m))}, where w isperfusion and c_(f) is the specific heat of the perfusate, V_(b) is thebead mean volumetric temperature during a cool-down period, t_(heat) isthe length of time for which heating is applicated and f(t) representsthe temporal form of the transient power applied to said heating meansas a function of time.

[0034] In accordance with certain embodiments, a method for determiningthermal properties of a medium comprises the steps of: (A) establishingreference parameters for measuring, comprising determining unperturbedtemperature of medium; (B) obtaining measurements of medium comprisingthe steps of: (1) causing the temperature of said medium to change froma first unperturbed temperature to a second temperature different fromsaid first temperature during an overall time period, (2) calculatingeffective thermal conductivity and diffusivity values of said mediumduring a plurality of time periods within said overall time period, (3)extrapolating the effective thermal conductivity and diffusivity valuescalculated in step (2) to the thermal conductivity and diffusivityvalues at a selected time to when the temperature of said medium isfirst caused to change so as to determine the extrapolated values of theintrinsic thermal conductivity and diffusivity of said medium, (4)calculating a perfusion of said medium during a selected time period ofsaid overall time period using said extrapolated intrinsic thermalconductivity and diffusivity, (5) recalculating the effective thermalconductivity and diffusivity values of said medium during said pluralityof time periods; using said calculated perfusion, (6) re-extrapolatingthe thermal conductivity and diffusivity values recalculated in step (5)to the intrinsic thermal conductivity and diffusivity values at saidselected time t_(o), (7) recalculating the perfusion of said mediumduring said selected time period using the intrinsic thermalconductivity and diffusivity values reextrapolated in step (6); and (8)repeating steps (5) through (7) until the recalculated intrinsic thermalconductivity and diffusivity values and the recalculated perfusion valueconverge to substantially non-changing values; (C) determining the needfor new reference parameters for medium.

[0035] In certain preferred embodiments the temperature change producedin said medium is constant and further wherein in steps (2) and (5) thethermal conductivity and diffusivity are calculated in accordance withthe following equation:${P(t)} = {\frac{4\pi \quad {ak}_{a}\Delta \quad T}{\frac{1}{5\gamma} + \frac{1}{1 + {\lambda \quad a}}}\left\lbrack {1 + \frac{\frac{a}{\sqrt{\pi \quad a_{a}}}{f(t)}}{\frac{1 - {\lambda^{2}a^{2}}}{5\gamma} + 1 + {\lambda \quad a}}} \right\rbrack}$

[0036] In other embodiments the temperature change produced in saidmedium is constant and further wherein in steps (4) and (7) theperfusion is calculated in accordance with the following equation:${P(t)} = {\frac{4\pi \quad {ak}_{a}\Delta \quad T}{\frac{1}{5\gamma} + \frac{1}{1 + {\lambda \quad a}}}\left\lbrack {1 + \frac{\frac{a}{\sqrt{\pi \quad a_{a}}}{f(t)}}{\frac{1 - {\lambda^{2}a^{2}}}{5\gamma} + 1 + {\lambda \quad a}}} \right\rbrack}$

[0037] In still other embodiments the temperature change produced insaid medium is constant and further wherein in step (4) and (7) theperfusion is calculated in accordance with the following equation, for atime period which is subsequent to the deactivation of the temperaturechanging means:$\frac{V_{b}(t)}{\Delta \quad T} = {\frac{a/\sqrt{\pi \quad \alpha_{m}}}{\frac{1 - {\lambda^{2}a^{2}}}{5\gamma} + 1 - {\lambda \quad a}}\begin{bmatrix}{\left\{ {{f\left( {t - t_{heat}} \right)} - {f(t)}} \right\} +} \\{\frac{a/\sqrt{\pi \quad a_{m}}}{\frac{1 - {\lambda^{2}a^{2}}}{5\gamma} + 1 + {\lambda \quad a}}\frac{\sqrt{t_{heat}}^{{- \lambda}\quad 2{am}^{t}}}{t\sqrt{t - t_{heat}}}}\end{bmatrix}}$

[0038] Other embodiments have the temperature change in said mediumproduced by activating a power source so as to produce a change in powerwhich is constant and further wherein in steps (2) and (5) the thermalconductivity and diffusivity are calculated in accordance with thefollowing equation:${V_{b}(t)} = {\frac{P_{o}}{4\pi \quad {ak}_{a}}\left\lbrack {\frac{1}{5\gamma} + \frac{1}{1 + {\lambda \quad a}} - {\frac{a/\sqrt{\pi \quad \alpha_{m}}}{1 - {\lambda^{2}a^{2}}}{f(t)}}} \right\rbrack}$

[0039] The temperature change in said medium may also be produced byactivating a power source so as to produce a change in power which isconstant and further wherein in steps (4) and (7) the perfusion iscalculated in accordance with the following equation:${V_{b}(t)} = {\frac{P_{o}}{4\pi \quad {ak}_{a}}\left\lbrack {\frac{1}{5\gamma} + \frac{1}{1 + {\lambda \quad a}} - {\frac{a/\sqrt{\pi \quad \alpha_{m}}}{1 - {\lambda^{2}a^{2}}}{f(t)}}} \right\rbrack}$

[0040] Other embodiments have the temperature change in said mediumproduced by activating a power source so as to produce a change in powerwhich is constant and further wherein in steps (4) and (7) the perfusionis calculated in accordance with the following equation, for a timeperiod which is subsequent to the deactivation of the power source:${V_{b}(t)} = {\frac{P_{o}}{4\pi \quad {ak}_{a}\sqrt{\pi \quad \alpha_{m}}}{\frac{1}{1 - {\lambda^{2}a^{2}}}\left\lbrack {{f\left( {t - t_{heat}} \right)} - {f(t)}} \right\rbrack}}$

[0041]FIG. 2 depicts a block diagram of showing the basic steps of theabove mentioned methods.

[0042] In the embodiment illustrated by FIG. 5, step (1) consists ofdetermining baseline conditions in the medium and establishing baselinecriteria based thereon. This step can involve numerous steps but thebasic purpose is to establish a reference for the medium that allfollowing measurements will be compared against. The criteria can comefrom the probe of the measuring device, can be user inputted, orobtained from other instrumentation. This step may also include the stepof calibrating the instrumentation used; that is, establishing baselinecriteria for the instrumentation.

[0043] Step (2) comprises of obtaining measurements of the medium, forexample, live tissue. In a preferred embodiment this comprises raisingthe temperature of the medium and monitoring the time, and powerrequired to raise and then maintain the new temperature. In some casesthis step may also include ceasing to heat the medium and monitoring thecool down rate. From this process properties of the medium such asthermal conductivity and rate of flow can be calculated. Thesemeasurements and calculations may be performed multiple times.

[0044] Step (3) comprises determining if new baseline criteria need tobe established. In a preferred embodiment the baseline conditions onwhich baseline criteria are based are monitored thru-out the method. Ifthere is a change indicating that conditions of the medium or otherconditions on which baseline criteria are based have changed,calculations and measurements based on the original baseline conditionsmay no longer be valid. Therefore it may be necessary to obtain a newbaseline. In certain embodiments step (3) comprises the steps of:comparing measurements taken and calculated to established baselinecriteria to existing measurements and determining if there has been achange in conditions. In other embodiments step (3) comprises the stepsof comparing measurements received from other instrumentation tobaseline criteria, and determining if there has been a change inconditions.

[0045] In certain embodiments the methods have an additional step (4)consisting of repeating the process again if new baseline criteria arerequired. This includes establishing new baseline criteria and obtainingnew measurements based on the new baseline criteria.

[0046] In accordance with certain embodiments, a method for determiningproperties of a medium comprises the steps of: determining baselineconditions and establishing baseline criteria for the medium; inducing atemperature change in the medium during a predetermined interval;calculating at least one selected intrinsic thermal property of saidmedium using data obtained at a first time period; calculatingseparately a perfusion rate of said medium using data obtained at asecond time period and said at least one calculated intrinsic thermalproperty, the effects of the perfusion of said medium at said secondtime period being greater than the effects of the perfusion of saidmedium at said first time period; and determining the need for newbaseline criteria for the medium. The invention may further compriserepeating the previous steps to obtain another perfusion rate of themedium when need for a new baseline is indicated.

[0047] In accordance with certain other embodiments, a method fordetermining properties of a medium with automatic recalibrationcomprises the steps: 1) measuring the temperature of the medium at afirst and second location; 2) determining if the temperatures at thefirst and second location are stable, wherein if the temperature ateither the first or second location are not stable then repeating step1; 3) raising the temperature of the medium at the second location apredetermined amount; 4) measuring the temperature at the first locationand calculating the power required to raise the temperature at thesecond location; 5) repeating step 4 for a set period of time; 6)calculating the intrinsic thermal conductivity of the medium; 7)calculating the rate of flow of the medium; 8) determining if thetemperature of the medium at the first location is stable, wherein ifthe temperature at the first location is not stable, then repeating step1; 9) determining if the change in power over time is less than anestablished maximum value, wherein if the change in power over time isnot less than the established maximum, then repeating step 1; 10)determining if the total time the measurements have been taken over isless than an established maximum, wherein if the total is not less thanthe established maximum, then repeating step 1; 11) repeating step 4.

[0048] In accordance with one embodiment, in a method for determiningproperties of a medium comprising the steps of: (1) causing thetemperature of said medium to change from a first unperturbedtemperature to a second temperature different from said firsttemperature during a first time period; (2) causing the temperature ofsaid medium to relax to a final unperturbed temperature during a secondtime period; (3) calculating an intrinsic thermal conductivity and adiffusivity of said medium during a first selected portion of said firstand second time periods; (4) calculating a perfusion of said medium at,at least a second selected portion of said first and second timeperiods, using said calculated intrinsic thermal conductivity anddiffusivity; (5) recalculating the intrinsic thermal conductivity anddiffusivity of said medium during said first selected portion of saidfirst and second time periods using said calculated perfusion; (6)recalculating the perfusion of said medium at least at said secondselected portion of said first and second time periods using saidrecalculated intrinsic thermal conductivity and diffusivity; and (7)repeating steps (5) and (6) until the recalculated intrinsic thermalconductivity and diffusivity and the recalculated perfusion eachconverge to a substantially non-changing value; an improvement comprisesthe steps of: (a) prior to step (1), establishing baseline criteria thatcorrespond to properties of the medium; and (b) periodically determiningthe need for and establishing new baseline criteria.

[0049] In accordance with certain embodiments, represented by the blockdiagram of FIG. 5, a method for determining properties of a mediumcomprises the steps of: (1) establishing baseline criteria for mediumconditions or properties, comprising: determining the thermalconductivity of a heating means, said heating means having apredetermined resistance versus temperature relationship, anddetermining the reference temperature of said medium when said heatingmeans is immersed in said medium and said medium is unheated; (2)obtaining measurements of medium comprising the steps of: applying powerto said heating means sufficiently rapidly to heat said means to avolume mean temperature above said reference temperature so that thepower necessary to maintain said volume mean temperature varies as afunction of time, determining the time varying relationship between thepower required to maintain said heating means at said volume meantemperature after said temperature has been reached and the time duringwhich said power is being applied thereto, determining the temperaturedifference between said volume mean temperature and said referencetemperature and determining the resistance of said heating means at saidvolume mean temperature, determining the thermal conductivity of saidmedium as a function of said temperature difference, of the resistanceof said heating means at said volume mean temperature, of said appliedpower in accordance with said time varying power and time relationship,of said predetermined thermal conductivity of said heating means, and ofat least one characteristic dimension of said heating means inaccordance with a thermal model of said heating means and said medium inwhich it is immersed wherein said heating means is treated as adistributed thermal mass and wherein heat conduction occurs in a coupledthermal system which comprises both the heating means and the adjacentregion of said medium which surrounds said heating means; and (3)determining need for new baseline criteria comprising evaluatingphysiological conditions that may materially affect the baselinecriteria. Examples of physiological conditions include but are notlimited to tissue and vascular damage, tissue edema, tissue scarformation, influence of a large vessel, change in vascular status suchas blood volume, vasodilation, and vasoconstriction; changes inperfusion, changes in blood pressure, changes in tissue pressure,changes in tissue temperature, changes in blood temperature, and changesin tissue metabolism.

[0050] In certain preferred embodiments step (3) further comprises thestep of evaluating measurement artifact conditions that may materiallyaffect the baseline criteria. Examples of measurement artifactconditions include but are not limited to sensor motion relative to thetissue, excessive sensor such as tissue contact force or capillarycollapse, insufficient sensor-tissue contact force such as artifactualtransduction of perfusion, sensor cross-talk, ambient temperaturechanges, electrical interference, instrumentation drift, automaticallyperform a recalibration, probe recalibration, and instrumentationrecalibration. In other embodiments the method further comprises step(4): repeating steps (1) and (2) when indicated by step (3).

[0051] In a certain preferred embodiment, in step (1), said referencetemperature is determined over a relatively short time period over whichit remains substantially constant and step (2) further including thesteps of: maintaining said volume mean temperature at a fixed,predetermined value above said reference temperature, said time varyingpower and time relationship being determined in terms of therelationship between the square of the voltage applied to said heatingmeans and the inverse square root of the time during which said voltageis being applied; determining a first characteristic Γ of saidrelationship representing the value of the power per unit volumegenerated by the heating means at a time t effectively equivalent to aninfinite time period following the application of said power to saidheating means; and further wherein said thermal conductivity of saidmedium is determined in accordance with the expression:$k = \frac{5}{\frac{15\Delta \quad T}{\Gamma \quad \overset{\_}{a^{2}}} - \frac{1.0}{k_{b}}}$

[0052] where k is the thermal conductivity of said medium, ΔT is thesaid fixed volume mean temperature difference, {overscore (a)} is theradius of a spherical heating means having a volume equivalent to theactual volume of said heating means, and k_(b) is said predeterminedthermal conductivity of said heating means.

[0053] In still other embodiments, in step (1), the step of determiningsaid reference temperature includes the steps of: measuring the voltageat said heating means in its unheated state; determining the currentthrough said heating means in its unheated state; determining theresistance of said heating means in its unheated state; and determiningsaid reference temperature in accordance with the said predeterminedresistance versus temperature relationship of said heating means.

[0054] In another embodiment according to step (2), the step ofmaintaining said volume mean temperature at said fixed value furtherincludes the steps of: preselecting a fixed value for said temperaturedifference; determining said volume mean temperature from said referencetemperature and said preselected fixed temperature difference;determining the resistance of said heating means at said volume meantemperature in accordance with said predetermined resistance versustemperature relationship; and maintaining the resistance of said heatingmeans at a substantially constant value equal to said determinedresistance whereby said volume mean temperature remains at asubstantially constant value.

[0055] In another embodiment wherein the time varying relationshipbetween the square of the voltage V_(h) ² and the inverse square root ofthe time t^(−1/2) is a substantially linear relationship of the formV_(h) ²(t)=m₁+m₂t^(−1/2); and further wherein said first characteristicΓ is determined in accordance with the expression:$\Gamma = \frac{m_{1}}{R_{h}\frac{4}{3}{\pi \left( \overset{\_}{a} \right)}^{3}}$

[0056] Other embodiments further include the steps of: predeterminingthe thermal diffusivity of said heating means; determining a secondcharacteristic β representing the slope of the time varying relationshipbetween the square of the voltage v_(h) ² and the inverse square root ofthe time t^(−1/2) at a time relatively shortly after the time at whichsaid power is applied; predetermining the non-dimensional relationshipbetween the expression β{square root}{square root over(α_(b))}/Γ{overscore (a)} wherein α_(b) is the predetermined thermaldiffusivity of said heating means; the expression k_(m)/k_(b), whereink_(m) is the thermal conductivity of said medium with no fluid flowingtherein; and the expression α_(b)/α_(m) where α_(m) is thermaldiffusivity of any medium which is to be determined; determining theactual value of β{square root}{square root over (α_(b))}/Γ{overscore(a)} and k_(m)/k_(b) at said volume mean temperature and furtherdetermining the value of α_(b)/α_(m) in accordance with saidpredetermined non-dimensional relationship; and determining the thermaldiffusivity α_(m) of said medium in accordance with the determined valueof α_(b)/α_(m).

[0057] In certain preferred embodiments time varying relationshipbetween the square of the voltage V_(h) ² and the inverse square root oftime t^(−1/2) is a substantially linear relationship of the form V_(h)²(t)=m₁+m₂t^(−1/2); and further wherein said first characteristic Γ isdetermined in accordance with the expression:${\Gamma = \frac{m_{1}}{R_{h}\frac{4}{3}{\pi \left( \overset{\_}{a} \right)}^{3}}};{and}$

[0058] said second characteristic β is determined in accordance with theexpression:$\beta = \frac{m_{2}}{R_{h}\frac{4}{3}{\pi \left( \overset{\_}{a} \right)}^{3}}$

[0059] In other embodiments the reference temperature varies with timeover a relatively long time period and further including the steps of:determining said reference temperature value over said time period;maintaining said volume mean temperature at a fixed, predeterminedvalue, said fixed value being greater than said reference temperatureover said time period; determining the time-varying temperaturedifference between said fixed volume mean temperature and saidtime-varying reference temperature; determining the fixed value of theresistance of said heating means at said volume mean temperature; anddetermining the thermal conductivity of said medium over said timeperiod in accordance with the expression:${k(t)} = \frac{5}{\frac{\Delta \quad {T(t)}R_{h}20\pi \quad \overset{\_}{a}}{V_{h}^{2}(t)} - \frac{1.0}{k_{b}}}$

[0060] where k(t) is the thermal conductivity of said medium, ΔT is saidtemperature difference, R_(h) is the said fixed resistance of saidheating means at said volume mean temperature, a is the radius of aspherical heating means having a volume equivalent to the actual volumeof said heating means, V_(h)(t) is the voltage at said heating meanswhere said power is applied, and k_(b) is said predetermined thermalconductivity of said heating means.

[0061] In some embodiments the step of determining said referencetemperature includes the steps of: immersing a temperature sensing meansin said medium at a region sufficiently remote from the immersed heatingmeans so that the temperature sensed by said sensing element is notmaterially affected by the raised temperature of said heating means,said sensing means having a predetermined resistance versus temperaturerelationship; determining over said time period the voltage at saidsensing means and the current through said sensing means; determiningthe reference temperature sensed by said sensing means over said timeperiod in accordance with the said predetermined resistance versustemperature relationship thereof.

[0062] In another embodiment, the steps thereof are first performed whenno fluid is flowing in said medium to determine the intrinsic thermalconductivity k_(m) of said medium and said steps are further performedover said time period when a fluid having a predetermined heat capacityis flowing in said medium to determine the effective thermalconductivity k_(eff)(t) of said medium; and further including the stepsof: predetermining the heat capacity C_(b) of said fluid; determiningthe ratio of k_(eff)(t)k_(m) over said time period; and determining therate of flow ω(t) of said fluid in said medium in accordance with theexpression:${\omega (t)} = {\left( {\frac{k_{eff}(t)}{k_{m}} - 1} \right)^{2}\frac{k_{m}}{{C_{b}\left( \overset{\_}{a} \right)}^{2}}}$

[0063] where ω(t) is measured in terms of the mass of fluid per unitvolume of the medium per unit time.

[0064] In another embodiment the reference temperature varies with timeover a relatively long time period and further including the steps of:determining said reference temperature over said time period;determining the said volume mean temperature over said time period as afunction of said reference temperature and a preselected fixed value ofsaid temperature difference; maintaining the resistance of said heatingmeans over said time period at a value such as to maintain thetemperature difference between said volume mean temperature and saidreference temperature at said preselected fixed value, said resistancevarying as a function of time; determining the thermal conductivity k(t)of said medium over said time period in accordance with the expression:${k(t)} = \frac{5}{\frac{\Delta \quad {T(t)}R_{h}20\pi \quad \overset{\_}{a}}{V_{h}^{2}(t)} - \frac{1.0}{k_{b}}}$

[0065] where ΔT is said temperature difference, R_(h)(t) is saidresistance of said heating means at said volume mean temperature,{overscore (a)} is the radius of a spherical heating means having avolume equivalent to the actual volume of said heating means, V_(h)(t)is the voltage at said heating means when said power is applied andk_(b) is the predetermined thermal conductivity of said heating means.

[0066] In another embodiment, the step of determining said referencetemperature includes the steps of: immersing a temperature sensing meansin said medium at a region sufficiently remote from the immersed heatingmeans so that the temperature sensed by said sensing element is notmaterially affected by the raised temperature of said heating means(referred to as sensor cross-talk), said sensing means having apredetermined resistance versus temperature relationship; determiningover said time period the voltage at said sensing means and the currentthrough said sensing means; determining the reference temperature sensedby said sensing means over said time period in accordance with the saidpredetermined resistance versus temperature relationship thereof.

[0067] In still other embodiments the steps thereof are first performedwhen no fluid is flowing in said medium to determine the intrinsicthermal conductivity k_(m) of said medium and said steps are furtherperformed over said time period when a fluid having a predetermined heatcapacity is flowing in said medium to determine the effective thermalconductivity k_(eff)(t) of said medium; and further including the stepsof: predetermining the heat capacity C_(b) of said fluid; determiningthe ratio of k_(eff)(t)/km over said time period; and determining therate of flow ω(t) of said fluid in said medium in accordance with theexpression:${\omega (t)} = {\left( {\frac{k_{eff}(t)}{k_{m}} - 1} \right)^{2}\frac{k_{m}}{{C_{b}\left( \overset{\_}{a} \right)}^{2}}}$

[0068] where ω(t) is measured in terms of the mass of the fluid per unitvolume of the medium per unit time.

[0069] In another embodiment, the reference temperature varies with timeover a relatively long time period and further including the steps of:immersing a temperature sensing means in said medium at a regionsufficiently remote from the immersed heating means so that thetemperature sensed by said sensing element is not affected by the raisedtemperature of said heating means, said sensing means having apredetermined resistance versus temperature relationship; determiningthe resistance of said sensing means over said time period; determiningthe reference temperature of said sensing means over said time period;determining the desired resistance of said heating means over said timeperiod as a function of the resistance of said sensing means and of apreselected fixed value of the resistance difference between theresistances of said sensing means and said heating means; maintainingthe resistance of said heating means at said desired resistance valueover said time period so that said resistance difference remains at saidpreselected fixed value, the resistance of said heating means varying asa function of time; determining the mean temperature of said heatingmeans over said time period at the said desired resistance value of saidheating means, said mean temperature varying as a function of time;determining the temperature difference between said mean temperature andsaid reference temperature over said time period, said temperaturedifference varying as a function of time; determining the thermalconductivity k(t) of said medium over said time period in accordancewith the expression:${k(t)} = \frac{5}{\frac{\Delta \quad {T(t)}R_{h}20\pi \quad \overset{\_}{a}}{V_{h}^{2}(t)} - \frac{1.0}{k_{b}}}$

[0070] where ΔT(t) is said temperature difference, R_(h)(t) is saidresistance of said heating means at said mean temperature, a is theradius of a spherical heating means having a volume equivalent to theactual volume of said heating means, V_(h)(t) is the voltage at saidheating means when said power is applied and k_(b) is the predeterminedthermal conductivity of said heating means.

[0071] In another embodiment, the step of determining said referencetemperature includes the steps of: immersing a temperature sensing meansin said medium at a region sufficiently remote from the immersed heatingmeans to that the temperature sensed by said sensing element is notaffected by the raised temperature of said heating means (i.e.: nosensor cross-talk), said sensing means having a predetermined resistanceversus temperature relationship; determining over said time period thevoltage at said sensing means and the current through said sensingmeans; determining the reference temperature sensed by said sensingmeans over said time period in accordance with the said predeterminedresistance versus temperature relationship thereof.

[0072] In other embodiments, the steps thereof are first performed whenno fluid is flowing in said medium to determine the intrinsic thermalconductivity k_(m) of said medium and said steps are further performedover said time period when a fluid having a predetermined heat capacityis flowing in said medium to determine the effective thermalconductivity k_(eff)(t) of said medium; and further including the stepsof: predetermining the heat capacity C_(b) of said fluid; determiningthe ratio of k_(eff)(t)/k_(m) over said time period; and determining therate of flow of said fluid in said medium in accordance with theexpression:${\omega (t)} = {\left( {\frac{k_{eff}(t)}{k_{m}} - 1} \right)^{2}\frac{k_{m}}{{C_{b}\left( \overset{\_}{a} \right)}^{2}}}$

[0073] where ω(t) is measured in terms of the mass of the fluid per unitvolume of medium per unit time.

[0074] A more specific preferred embodiment can be seen in the blockdiagram of FIG. 6 wherein the method comprises the steps of: 1)measuring T1 and T2, the temperatures at a first and second location; 2)determining if T1 and T2, the temperatures at the first and secondlocations are stable; 3) if T1 and T2 are not stable, then repeatingstep 1; 4) if T1 and T2 are stable, then setting T2 to a differenttemperature, T2+DT; 5) measuring T1 and calculating P2, the powerrequired to change the temperature at the second location; 6)determining if P2 data has been acquired for a selected time period(i.e.: 10 seconds); 7) if 10 seconds of P2 data not acquired, thenrepeat step 5; 8) if 10 seconds of P2 data has been acquired, thencalculating intrinsic thermal conductivity of the medium, K_(m); 9)calculating perfusion, w; 10) determining if T1 is stable; 11) if T1 isnot stable, then repeating step 1; 12) if T1 is stable, then determiningif dP2/dt is less than dP/dt(max); 13) if dP2/dt is not less thandP/dt(max), then repeating step 1; 14) if dP2/dt is less thandP/dt(max), then determining if time, t, is less than establishedmaximum time, t(max); 15) if t is not less than t(max), then repeatingstep 1; 16) if t is less than t(max), then repeating step 5.

[0075] In another embodiment, a method for determining properties of amedium comprises the steps of: (1) establishing baseline criteriacorresponding to baseline conditions of the medium, comprising:determining the thermal conductivity of a heating means as a function oftemperature, said heating means having a predetermined resistance versustemperature relationship; contacting said medium with said heatingmeans; and determining the reference temperature of said medium whensaid medium is unheated; (2) obtaining measurements of medium comprisingthe steps of: applying power to said heating means sufficiently rapidlyto heat said means to a temperature above said reference temperature sothat the power necessary to maintain said temperature varies as afunction of time; determining the time varying power and timerelationship between the power required to maintain said temperature andthe time during which said power is applied to said heating means;determining the temperature difference between said temperature and saidreference; determining the thermal conductivity of said medium as afunction of said temperature difference, and of said applied power inaccordance with said time varying power and time relationship; and (3)determining need for new baseline criteria comprising evaluatingphysiological conditions and/or artifact conditions changes in which mayaffect the baseline conditions of the medium.

[0076] Referring to FIG. 7, a method for determining properties of amedium with automatic recalibration comprises the steps of: 1) providingan apparatus for determining properties of a medium, comprising: acomputer 50, a display 52 in electrical communication with the computer,a detector circuit 54 in electrical communication with the computer 50,a printer 56 in electrical communication with the detector circuit 54, afirst power supply 58 in electrical communication with the detectorcircuit 54, a second power supply 60 in electrical communication withthe computer 50, display 52, detector circuit 54, and printer 56; akeypad 62 in electrical communication with the detector circuit 54, anda probe 64 in electrical communication with the detector circuit 54; 2)inserting the probe into the medium; 3) having/operating the deviceperform the following steps: A) measuring the temperature of the mediumat a first and second location; B) determining if the temperatures atthe first and second location are stable, wherein if the temperature ateither the first or second location are not stable then repeating step1; C) raising the temperature of the medium at the second location apredetermined amount; D) measuring the temperature at the first locationand calculating the perfusion at the second location; E) repeating stepD for a set period of time; F) calculating the intrinsic thermalconductivity of the medium; G) calculating the rate of flow of themedium; H) determining if the temperature of the medium at the firstlocation is stable, wherein if the temperature at the first location isnot stable, then repeating step 1; I) determining if the rate ofperfusion is less than an established maximum value, wherein if rate ofperfusion is not less than the established maximum, then repeating stepA; J) determining if the total time the measurements have been takenover is less than an established maximum, wherein if the total is notless than the established maximum, then repeating step A; K) repeatingstep D.

[0077] In accordance with further embodiments, an apparatus fordetermining physical characteristics of a medium is provided. One suchapparatus comprises: temperature sensing means immersed in or contactingthe medium for sensing the reference temperature of the medium when themedium is unheated; heating means immersed in the medium for heating themedium, the heating means having a predetermined thermal conductivity, apredetermined thermal diffusivity and a predetermined characteristicdimension; means for applying power to the heating means sufficientlyrapidly to raise the temperature of the heating means to a volume meantemperature above the reference temperature so that the power necessaryto maintain the volume mean temperature varies as a function of time;data processing means for determining the temperature difference betweenthe volume mean temperature and the reference temperature, fordetermining the resistance of the heating means at the volume meantemperature and for determining the time varying relationship betweenthe power required to maintain the heating means at the volume meantemperature after the temperature has been reached and the time duringwhich the power is being applied thereto; the data processing meansfurther being responsive to the temperature difference, the heatingmeans resistance, the applied power in accordance with the time varyingpower and time relationship, the predetermined thermal conductivity ofthe heating means, a change in reference parameters, and thepredetermined characteristic dimension of the heating means fordetermining the thermal conductivity of the medium in accordance with athermal model of the heating means and the medium wherein the heatingmeans is treated as a distributed thermal mass and wherein heatconduction occurs in a coupled thermal system which comprises both theheating means and the adjacent region of the medium which surrounds theheating means.

[0078] In certain embodiments the sensing means and the heating meanscomprises a single element capable of sensing the temperature of themedium and of heating the medium. An example of such a single element isa thermistor bead element, for example, of the type havingcharacteristics referenced in above-mentioned U.S. Pat. Nos. 4,059,982and 4,852,027. In other embodiments the apparatus further includesvolume means for maintaining the mean temperature at a fixed,predetermined value above the reference temperature, the referencetemperature being determined and the volume mean temperature beingmaintained over a relatively short time interval during which thereference temperature remains substantially constant whereby thetemperature difference and the resistance of the heating means alsoremain substantially constant. Variations of such an embodiment furtherinclude: means for determining the time varying power and timerelationship in terms of the relationship between the square of thevoltage applied to the heating means and the inverse square root of thetime during which the voltage is being applied; means for determining afirst characteristic Γ of the relationship representing the value of thepower per unit volume generated by the heating means at a time teffectively equivalent to an infinite time period following theapplication of the power to the heating means; and means for determiningthe thermal conductivity of the medium in accordance with theexpression:$k = \frac{5}{\frac{15\Delta \quad T}{\Gamma \quad \overset{\_}{a^{2}}} - \frac{1.0}{k_{b}}}$

[0079] where k is the thermal conductivity of the medium, ΔT is the meantemperature difference, a is the radius of a spherical heating meanshaving a volume equivalent to the actual volume of the heating means andk_(b) is the predetermined thermal conductivity of the heating means.

[0080] In still other embodiments, the time varying relationship betweenthe square of the voltage V_(h) ² and the inverse square root of thetime t.sup.−1/2 is a substantially linear relationship of the form V_(h)²(t)=m₁+m₂ t^(−1/2); and the first characteristic determining meansincludes means for determining the first characteristic Γ in accordancewith the expression:$\Gamma = \frac{m_{1}}{R_{h}\frac{4}{3}{\pi \left( \overset{\_}{a} \right)}^{3}}$

[0081] where R_(h) is the resistance of the heating means at the volumemean temperature.

[0082] Variations of these embodiments further include: means fordetermining a second characteristic β in accordance with the expression:$\beta = \frac{m_{2}}{R_{h}\frac{4}{3}{\pi \left( \overset{\_}{a} \right)}^{3}}$

[0083] memory storage means for storing the non-dimensionalpredeterminable relationship between the expression β{squareroot}{square root over (α_(b))}/Γ{overscore (a)} wherein α_(b) is thepredetermined thermal diffusivity of the heating means; the expressionk_(m)/k_(b), wherein k_(m) is the thermal conductivity of the mediumwith no fluid flowing therein; and the expression α_(b)/α_(m) is thethermal diffusivity of any medium which is to be determined; and meansfor determining the actual value of the expression β{square root}{squareroot over (α_(b))}/Γ{overscore (a)} and k_(m)/k_(b) and for determiningthe actual value of α_(b)/α_(m) from the memory storage means; and meansresponsive to the value of α_(b)/α_(m) for determining the thermaldiffusivity α_(m) of the medium.

[0084] In other embodiments the sensing means and the heating meanscomprise: a first heating element immersed at a first region of themedium; and a second element immersed at a second region of the mediumsufficiently remote from the first region as to be not affected orminimally affected by the heating of the first element. In certainembodiments the first and second elements are thermistor bead elements.

[0085] Other variations for use over a relatively long time periodduring which the reference temperature varies with time and wherein thesecond element determines the reference temperature over the timeperiod; further include: means for maintaining the volume meantemperature and the resistance of the heating means at the volume meantemperature at fixed predetermined values over the time period duringwhich the reference temperature varies whereby the temperaturedifference there between varies over the time period.

[0086] Variations of such embodiments have the data processing meansdetermine the thermal conductivity of the medium over the time period inaccordance with the expression:${k(t)} = \frac{5}{\frac{\Delta \quad {T(t)}R_{h}20\quad \pi \quad \overset{\_}{a}}{V_{h}^{2}(t)} - \frac{1.0}{k_{b}}}$

[0087] where k(t) is the thermal conductivity, ΔT(t) is the temperaturedifference, R_(h) is the resistance of the heating means at the meantemperature, V_(h)(t) is the voltage at the heating means as power isapplied thereto, a is the radius of a spherical heating means having avolume equivalent to the actual volume of the heating means and k_(b) isthe predetermined thermal conductivity of the heating means. The dataprocessing system may also include means for determining the intrinsicthermal conductivity k_(m) of the medium when no fluid is flowingtherein; means for determining the effective thermal conductivityk_(eff)(t) of the medium when a fluid having a predetermined heatcapacity is flowing therein; means for determining the ratio ofk_(eff)(t)/km over the time period; and means for determining the rateof flow ω(t) of the fluid in the medium in accordance with theexpression:${\omega (t)} = {\left( {\frac{k_{eff}(t)}{k_{m}} - 1} \right)^{2}\frac{k_{m}}{{C_{b}\left( \overset{\_}{a} \right)}^{2}}}$

[0088] where C_(b) is the predetermined heat capacity.

[0089] Other embodiments for use over a relatively long time periodduring which the reference temperature varies with time wherein thesecond element determines the reference temperature over the timeperiod; and may further include means for determining the volume meantemperature over the time period as a function of the referencetemperature and a preselected fixed value of the temperature difference;means for maintaining the resistance of the first element over the timeperiod at a value such as to maintain the temperature difference betweenthe volume mean temperature and the reference temperature at thepreselected fixed value, the resistance varying as a function of time;and means for determining the thermal conductivity of the medium overthe time period in accordance with the expression:${k(t)} = \frac{5}{\frac{\Delta \quad {T(t)}R_{h}20\quad \pi \quad \overset{\_}{a}}{V_{h}^{2}(t)} - \frac{1.0}{k_{b}}}$

[0090] where ΔT is the temperature difference, R_(h)(t) is theresistance of the heating means at the volume mean temperature,{overscore (a)} is the radius of a spherical heating means having avolume equivalent to the actual volume of the first element, V_(h)(t) isthe voltage at the first element when power is applied thereto, andk_(b) is the predetermined thermal conductivity of the first element.The data processing system may include means for determining theintrinsic thermal conductivity k_(m) of the medium when no fluid isflowing therein; means for determining the effective thermalconductivity k_(eff)(t) of the medium when a fluid having apredetermined heat capacity is flowing therein; means for determiningthe ratio of k_(eff)(t)/k_(m) over the time period; and means fordetermining the rate of flow ω(t) of the fluid in the medium inaccordance with the expression:${\omega (t)} = {\left( {\frac{k_{eff}(t)}{k_{m}} - 1} \right)^{2}\frac{k_{m}}{{C_{b}\left( \overset{\_}{a} \right)}^{2}}}$

[0091] where C_(b) is the predetermined heat capacity.

[0092] Still other embodiments for use over a relatively long timeperiod during which the reference temperature varies with time whereinthe second element determines the reference temperature over the timeperiod; further include means for determining the resistance of thesecond element over the time period; means for determining the desiredresistance of the first element over the time period as a function ofthe resistance of the second element and of a preselected fixed value ofthe resistance difference between the resistances of the second and thefirst elements; means for maintaining the resistance of the firstelement at the desired resistance so that the resistance difference ismaintained at the predetermined fixed value, the resistance of the firstelement varying as a function of time; means for determining the volumemean temperature of the first element over the time period at thedesired resistance of the first element, the volume mean temperaturevarying as a function of time; means for determining the temperaturedifference between the volume mean temperature and the referencetemperature over the time period, the temperature difference varying asa function of time; means for determining the thermal conductivity ofthe medium over the time period in accordance with the expression:${k(t)} = \frac{5}{\frac{\Delta \quad {T(t)}R_{h}20\quad \pi \quad \overset{\_}{a}}{V_{h}^{2}(t)} - \frac{1.0}{k_{b}}}$

[0093] where ΔT(t) is the temperature difference, R_(h)(t) is theresistance of the heating means at the volume mean temperature, a is theradius, of a spherical heating means having a volume equivalent to theactual volume of the first element, V_(h)(t) is the voltage at the firstelement when power is applied thereto, and k_(b) is the predeterminedthermal conductivity of the first element. The data processing systemmay include means for determining the intrinsic thermal conductivityk_(m) of the medium when no fluid is flowing therein; means fordetermining the effective thermal conductivity k_(eff)(t) of the mediumwhen a fluid having a predetermined heat capacity is flowing therein;means for determining the ratio of k_(eff)(t)/k_(m) over the timeperiod; and means for determining the rate of flow ω(t) of the fluid inthe medium in accordance with the expression:${\omega (t)} = {\left( {\frac{k_{eff}(t)}{k_{m}} - 1} \right)^{2}\frac{k_{m}}{{C_{b}\left( \overset{\_}{a} \right)}^{2}}}$

[0094] where C_(b) is the predetermined heat capacity.

[0095] Referring again to FIG. 7, apparatus for determining thermalproperties of living tissue in accordance with certain preferredembodiments will be described. An apparatus for determining propertiesof a medium, comprises: a computer 50; a display 52 in electricalcommunication with the computer 50; a detector circuit 54 in electricalcommunication with the computer 50; a printer 56 communicating withprinted tape slot 63 (FIG. 1) and in electrical communication with thedetector circuit 54; a first power supply 58 in electrical communicationwith the detector circuit 54; a second power supply 60 in electricalcommunication with the computer 50, display 52, detector circuit 54, andprinter 56; a keypad 62 in electrical communication with the detectorcircuit 54; and a probe 64 in electrical communication with the detectorcircuit 54. In certain embodiments the apparatus further comprises anexternal serial port 66 in electrical communication with the detectorcircuit 54. In other embodiments the apparatus further comprises anexternal output. This output may be either digital or analog.

[0096] The computer 50 may be any number of suitable microprocessortypes, which may include optional peripheral devices for input andoutput of data. The computer illustrated is a single boardmicroprocessor. The preferred computer may also comprise a first andsecond serial port. The display 52 may be any number of types, forexample, a flat panel display. The first power supply 58 is an isolatedpower supply and the second power supply 60 is an un-isolated powersupply.

[0097] In a preferred embodiment, the probe 64 comprises first andsecond thermistors 106 and 176, respectively, (FIGS. 8 and 9) incommunication with a control circuit 72. One example of thermistors thatcan be used with this embodiment are B35 and BR11 manufactured byThermometrics, Inc. (Edison, N.J.). One example of a probe includingsuch thermistors is shown in the above referenced U.S. Pat. No.5,035,514. The detector circuit 54 comprises: an isolated component 68comprising: a processor 70, the control circuit 72 in electricalcommunication with the processor 70, and at least one analog to digitalconverter 74; and an un-isolated component 76, in electricalcommunication with the processor 70 of the isolated component,comprising: a keyboard controller 78, a serial port 80, a serial portmultiplexor 82, and a digital to analog converter 84.

[0098] The control circuit 72 will be referenced in connection withFIGS. 7 and 8. The control circuit serves to selectively measuretemperature on or raise the temperature of the first or heat thermistor106 of the probe 64.

[0099] A circuit for a Heat Thermistor Control Circuit 72 shown in FIG.7, is also shown schematically in FIG. 8. The current source circuit 100measures temperature using the thermistor 106 located in the probe 64.The circuitry of box 105 is the interface of the heat thermistor controlcircuit 72 with the thermistor 106. The functionality of the controlcircuit is controlled using switches A through F. The control circuitfurther comprises first 140 and second 145 op-amps in connection with ascaling network 110, an integrator 115, control resistor 150, and acurrent source 125. The probe 64 and thermistor 106 are connected tocontrol circuit 72 through the probe interface 105, switch C and theconnector 53 shown in FIG. 1.

[0100] In a passive temperature monitoring or sense mode, referring toFIG. 8, the thermistor 106 is connected to the sense current source 100and to ground 102. Two precision resistors 150 and the 2.5 KOhm resistorshown between the current source and switch D are connected in series aswell. The position of each switch for the sense (or unheated) mode isdescribed in Table 1-1. TABLE 1-1 Switch Positions for Sense Mode SwitchPosition A right, connecting fixed resistor to thermistor B left,selecting thermistor C right, connecting thermistor to ground D left,connecting fixed resistor to current source E up, disconnecting feedbackloop F closed, opamp as amplifier not integrator

[0101] In the self-heating or heat mode, the resistor 150 and thethermistor 106 are connected to the current source 125 and, once thescaling network 110 is set for the desired level of amplification, therest of the control loop is closed using the switches as described inTable 1-2. TABLE 1-2 Switch Position for Heat Mode Switch Position Aright, connecting fixed resistor to thermistor B left, selectingthermistor C left, connecting thermistor to current sink D right,connecting fixed resistor to 5 V E down, closing feedback loop F open,opamp as integrator

[0102] Element 103, unused in both the sense and heat modes asdescribed, is a simulator for circuit testing purposes. Switch A ismoved to the left position only for testing purposes.

[0103]FIG. 9 shows a schematic of an embodiment of a thermal sensor andsafety circuit that comprises another part of the control circuit of theDetector Circuit 54 as shown in FIG. 7. The thermal sensor and safetycircuit consist of a current source 170 for measuring the temperaturewith the second or sense thermistor 176 of the probe 64 (FIG. 7); a setof calibration resistors 185, 190; and a safety circuit 195 that gives asignal or terminates operation if the voltage applied to thermistor 176is outside of a preset range. The second thermistor 176 connects throughthe connector 53 shown in FIG. 1.

[0104] As perfusion measurements are being taken and time passes,physiological, sensor and instrument conditions change and recalibrationis necessary. Referring again to FIGS. 3 and 4, the physiological orsensor and instrument artifact conditions are examples of conditionsthat may change and affect established baseline conditions. One or moresuch conditions are monitored and recalibration is initiated when avalue or values associated with these monitored conditions fall outsideof a predetermined range.

[0105] In the mode of FIG. 3, physiologic conditions are monitored andwhen the resulting value or a weighted combination of values fall withina predetermined range, that is when the monitored conditions do notmaterially affect or degrade accuracy, recalibration is not therebyindicated. One or more measurement artifact conditions are alsomonitored and when the resulting value or weighted combination of thesevalues are within a preset acceptable range, that is when perfusionmeasurement accuracy is not materially affected or degraded by artifactconditions, recalibration is again not indicated. Perfusion measurementsare deemed reliable.

[0106] When either or both of the values resulting from measurement ofone or more physiologic conditions and the values resulting frommeasurement of artifact conditions fall outside of the preset ranges,indicating a degradation of accuracy of the perfusion measurements,recalibration is indicated. The perfusion sensor is calibrated inresponse to a degradation of accuracy due to physiologic conditions andthe instrument is calibrated in response to a degradation of accuracydue to sensor or instrument artifact conditions that adversely affectperfusion measurement. Calibration and recalibration may be initiatedmanually in response to a signal provided by the system or initiatedautomatically by the system.

[0107] In the mode of FIG. 4, one or more physiologic, sensor andinstrument conditions are monitored. When the resulting value or valuesare within an acceptable range, indicating reliability of perfusionmeasurements, perfusion measurements are made. When the resulting valueor values are outside of the acceptable range additional inquiry isindicated. The system determines if instrument conditions contribute asubstantial component to the degradation. If not, recalibration in situof the perfusion sensor is indicated. If so, recalibration of theinstrumentation is indicated. Calibration and recalibration of thesensor and/or the instrumentation may be initiated manually in responseto a signal provided by the system or initiated automatically by thesystem.

[0108] The present invention is described above in terms of specificembodiments. It is anticipated that other uses alterations andmodifications will be apparent to those skilled in the art given thebenefit of this disclosure. It is intended that the following claims beread as covering such other uses alterations and modifications as fallwithin the true spirit and scope of the invention.

1. A method for determining perfusion in living tissue comprising thesteps of: (1) establishing baseline criteria, comprising (A) determiningan unperturbed temperature of the tissue; (B) causing the temperature ofthe tissue to change from a first unperturbed temperature to a secondtemperature different from said first temperature for a time period, and(C) determining a value or values for one or more thermal properties oftissue during a first selected portion of said time period; (2)calculating a perfusion value for the tissue at a second selectedportion of said time period using said thermal property value or values,and (3) evaluating one or more physiological and artifactual conditionsto determine if baseline criteria established by step (1) are materiallyaffected by said conditions and if so repeating step (1).
 2. A methodfor determining perfusion in living tissue comprising the steps of: (1)establishing thermal baseline criteria corresponding to thermalconditions of the tissue comprising determining an unperturbed tissuetemperature; (2) causing the temperature of a volume of the tissue tochange from the unperturbed temperature to a second temperaturedifferent from the unperturbed temperature during a time interval; (3)calculating at least one of an intrinsic thermal conductivity value anda thermal diffusivity value for said volume of tissue during a firstselected portion of said time interval; (4) calculating perfusion insaid volume of tissue at a second selected portion of said time intervalusing said value; (5) determining need for new baseline criteria for thetissue comprising evaluating one or both of physiologic and artifactconditions; and (6) repeating step (1) when indicated by step (5).
 3. Amethod for the periodic recalibration of perfusion measurement in tissuecomprising the steps of: (a) performing calibration of one or both of aperfusion sensor in thermal contact with the tissue and a perfusionmonitoring instrument; (b) measuring perfusion in tissue; (c)automatically recognizing one or more of physiologic and artifactconditions under which the calibration is no longer valid; (d)automatically performing a recalibration of one or both of the sensorand the instrument when the recognition of conditions indicates that thecalibration is no longer valid; and (d) repeating step (b).
 4. A methodaccording to claim 3 wherein the physiologic conditions are one or moreof tissue and vascular damage, tissue edema, tissue scar formation,influence of a large vessel, change in vascular status, blood volume,vasodilation, vasoconstriction, changes in perfusion, changes in bloodpressure, changes in tissue pressure, changes in tissue temperature,changes in blood temperature and changes in tissue metabolism.
 5. Amethod according to claim 3 or 4 wherein the artifact conditions are oneor more of sensor motion relative to the tissue, excessive sensor-tissuecontact force inducing capillary collapse, insufficient sensor-tissuecontact force resulting in insufficient sensor-tissue thermalcommunication, artifactual transduction of perfusion, sensor cross-talk,ambient temperature changes, electrical interference, andinstrumentation drift.
 6. A method for determining blood flow in tissuewith automatic recalibration comprising the steps of: (1) providing anapparatus for determining properties of tissue, comprising: a computer;a display in electrical communication with the computer; a detectorcircuit in electrical communication with the computer; a power supply inelectrical communication, with the display and detector circuit; akeypad in electrical communication with the detector circuit; and aprobe in electrical communication with the detector circuit; (2)inserting the probe into the tissue; (3) operating the device to performthe following steps: (A) measuring the unperturbed temperature of thetissue at a selected location; (B) determining if the temperature at thelocation is stable, wherein if the temperature is not stable thenrepeating step (A); (C) raising the temperature of the tissue at thelocation a predetermined amount; (D) measuring the elevated temperatureat the location and calculating perfusion; (E) repeating step (D) for aperiod of time; (F) determining if the temperature of the tissue at thelocation is stable, wherein if the temperature is not stable, thenrepeating step (A); (G) determining if a function of the power requiredin step (C) to raise the temperature of the tissue is less than anestablished maximum value, wherein if not less, then repeating step (A);(H) determining if the total time the measurements have been taken overis less than an established maximum, wherein if the total is not lessthan the established maximum, then repeating step (A); (I) repeatingstep (D).
 7. In a method for determining flow in tissue, a method forautomatic recalibration comprising the steps of: (1) measuring theunperturbed temperature of the tissue at a selected location; (2)determining if the temperature at the location is stable, wherein if thetemperature is not stable then repeating step 1; (3) raising thetemperature of the tissue at the location a predetermined amount; (4)measuring the elevated temperature at the location and calculating theperfusion; (5) determining if the temperature of the tissue at thelocation is stable, wherein if the temperature is not stable, thenrepeating step 1; (6) determining if a function of the power required instep (3) to raise the temperature of the tissue is less than anestablished maximum value, wherein if not less, then repeating step 1;(7) determining if the total time over which the measurements have beentaken is less than an established maximum, wherein if the total is notless than the established maximum, then repeating step 1; (8) repeatingstep
 3. 8. A method for monitoring perfusion in living tissuecomprising: determining baseline thermal conditions for a selectedtissue location and establishing baseline criteria based thereon;raising the temperature in said tissue location to a value above saidthermal baseline; computing values associated with one or more selectedthermal properties of the tissue location; computing blood flow using avalue that is a function of the power required by said raising step andone or more of the selected thermal property values; evaluating one ormore conditions that may significantly change one or more of the thermalbaseline and the selected thermal property values; and determining theneed for new baseline criteria using data from said evaluating step. 9.A method according to claim 8 further comprising the steps of: repeatingthe second said computing step until the second said determining stepindicates a need for new baseline criteria; when a need for new baselinecriteria is indicated discontinuing said raising step until said tissuelocation returns to an unperturbed state; and repeating the first saiddetermining step.
 10. A method according to claim 8 wherein saidevaluating step comprises evaluating selected artifact conditions forrecognizing artifact conditions under which the established thermalbaseline is no longer valid.
 11. A method according to claim 10 whereinartifact conditions include one or more of: ambient temperature changes,electrical interference, instrumentation drift, excessive sensor-tissuecontact force that can induce capillary collapse, insufficientsensor-tissue contact force that can result in artifactual transductionof perfusion, cross-talk between sensors, and motion of the sensorrelative to the tissue.
 12. The method of claim 8 wherein saidevaluating step comprises evaluating selected physiological conditionsfor recognizing conditions under which the established thermal baselineis no longer valid.
 13. A method according to claim 12 wherein saidevaluating step comprises evaluating selected artifact conditions forrecognizing artifact conditions under which the established thermalbaseline is no longer valid.
 14. A method according to claim 12 whereinphysiological conditions include one or more of: tissue and vasculardamage, tissue edema, tissue scar formation, influence of a largevessel, change in vascular status (e.g.: blood volume, vasodilation, andvasoconstriction), changes in perfusion, changes in blood pressure,changes in tissue pressure, changes in tissue temperature, changes inblood temperature, and changes in tissue metabolism.
 15. A methodaccording to any one of claims 9, 10, 11, 12, 13, or 14 furthercomprising the step of automatically recalibrating baseline criteria forone or more of the probe and the instrumentation based on the results ofthe second said determining step.
 16. In a method for determining bloodflow in tissue comprising the steps of: (1) causing temperature in thetissue to change from a first unperturbed temperature to a secondtemperature different from said first temperature during a time period;(2) calculating at least one of an intrinsic thermal conductivity and adiffusivity of the tissue during a first selected portion of said timeperiod; (3) calculating a perfusion of the tissue at, at least a secondselected portion of said time period, using said calculated intrinsicthermal conductivity and/or diffusivity; (4) recalculating the intrinsicthermal conductivity and diffusivity of the tissue using said calculatedperfusion; (5) recalculating the perfusion of the tissue using saidrecalculated intrinsic thermal conductivity and diffusivity; and (6)repeating steps (4) and (5) until the recalculated intrinsic thermalconductivity and diffusivity and the recalculated perfusion eachconverge to a substantially non-changing value; the improvementcomprising the steps of: (a) prior to step (1), establishing baselinecriteria corresponding to baseline thermal conditions of the tissue; and(b) periodically determining the need for and establishing new baselinecriteria.
 17. A method for determining blood flow in tissue comprisingthe steps of: (1) establishing baseline criteria for the tissue,comprising: determining the thermal conductivity of a heating means,said heating means having a predetermined resistance versus temperaturerelationship; immersing said heating means in the tissue; anddetermining the reference temperature of the tissue when the tissue isunheated; (2) obtaining measurements of the tissue comprising the stepsof: applying power to said heating means sufficiently rapidly to heatsaid means to a temperature above said reference temperature so that thepower necessary to maintain said temperature varies as a function oftime; determining the time varying relationship between the powerrequired to maintain said heating means at said temperature after saidtemperature has been reached and the time during which said power isbeing applied thereto; determining the temperature difference betweensaid temperature and said reference temperature and determining theresistance of said heating means at said temperature; determining thethermal conductivity of the tissue as a function of said temperaturedifference, of the resistance of said heating means at said temperature,of said applied power in accordance with said time varying power andtime relationship, of said predetermined thermal conductivity of saidheating means, and of at least one characteristic dimension of saidheating means in accordance with a thermal model of said heating meansand the tissue in which it is immersed wherein said heating means istreated as a distributed thermal mass and wherein heat conduction occursin a coupled thermal system which comprises both the heating means andthe adjacent region of the tissue which surrounds said heating means;and (3) determining need for new baseline criteria for tissue comprisingevaluating one or both of measurement artifact conditions andphysiological conditions.
 18. The method of claim 17, further comprisingthe step: (4) repeating steps (1) and (2) when indicated by step (3) 19.A method in accordance with claim 17, wherein step (1), the step ofdetermining said reference temperature includes the steps of applying aconstant current or voltage through said heating means in its unheatedstate; measuring the voltage or current at said heating means in itsunheated state; determining the resistance of said heating means in itsunheated state; and determining said reference temperature in accordancewith the said predetermined resistance versus temperature relationshipof said heating means.
 20. A method in accordance with claim 17, wherein step (2), the step of maintaining said temperature at said fixedvalue further includes the steps of preselecting a fixed value for saidtemperature difference; determining said maintained temperature fromsaid reference temperature and said preselected fixed temperaturedifference; determining the resistance of said heating means at saidmaintained temperature in accordance with said predetermined resistanceversus temperature relationship; and maintaining the resistance of saidheating means at a substantially constant value equal to said determinedresistance whereby said maintained temperature remains at asubstantially constant value.
 21. A method in accordance with claim 17,wherein said reference temperature varies with time over a relativelylong time period and further including the steps of determining saidreference temperature value over said time period; maintaining saidtemperature at a fixed, predetermined value, said fixed value beinggreater than said reference temperature over said time period;determining the time-varying temperature difference between said fixedtemperature and said time-varying reference temperature; determining thefixed value of the resistance of said heating means at said fixedtemperature; and determining the thermal conductivity of the tissue oversaid time period in accordance with the expression${k(t)} = \frac{5}{\frac{\Delta \quad {T(t)}R_{h}20\quad \pi \quad \overset{\_}{a}}{V_{h}^{2}(t)} - \frac{1.0}{k_{b}}}$

where k(t) is the thermal conductivity of the tissue, ΔT is saidtemperature difference, R_(h) is the said fixed resistance of saidheating means at said fixed temperature, a is the radius of a sphericalheating means having a volume equivalent to the actual volume of saidheating means, V_(h)(t) is the voltage at said heating means where saidpower is applied, and kb is said predetermined thermal conductivity ofsaid heating means.
 22. A method in accordance with claim 21, whereinthe step of determining said reference temperature includes the steps ofimmersing a temperature sensing means in the tissue at a regionsufficiently remote from the immersed heating means so that thetemperature sensed by said sensing element is not affected by the raisedtemperature of said heating means, said sensing means having apredetermined resistance versus temperature relationship; determiningover said time period the voltage at said sensing means and the currentthrough said sensing means; determining the reference temperature sensedby said sensing means over said time period in accordance with the saidpredetermined resistance versus temperature relationship thereof.
 23. Amethod in accordance with claim 17, wherein said reference temperaturevaries with time over a relatively long time period and furtherincluding the steps of determining said reference temperature over saidtime period; determining the said maintained temperature over said timeperiod as a function of said reference temperature and a preselectedfixed value of said temperature difference; maintaining the resistanceof said heating means over said time period at a value such as tomaintain the temperature difference between said maintained temperatureand said reference temperature at said preselected fixed value, saidresistance varying as a function of time; determining the thermalconductivity k(t) of the tissue over said time period in accordance withthe expression:${k(t)} = \frac{5}{\frac{\Delta \quad {T(t)}R_{h}20\quad \pi \quad \overset{\_}{a}}{V_{h}^{2}(t)} - \frac{1.0}{k_{b}}}$

where ΔT is said temperature difference, R_(h)(t) is said resistance ofsaid heating means at said maintained temperature, a is the radius of aspherical heating means having a volume equivalent to the actual volumeof said heating means, V_(h)(t) is the voltage at said heating meanswhen said power is applied and kb is the predetermined thermalconductivity of said heating means.
 24. A method in accordance withclaim 23, wherein the step of determining said reference temperatureincludes the steps of immersing a temperature sensing means in thetissue at a region sufficiently remote from the immersed heating meansso that the temperature sensed by said sensing element is not affectedby the raised temperature of said heating means, said sensing meanshaving a predetermined resistance versus temperature relationship;determining over said time period the voltage at said sensing means andthe current through said sensing means; determining the referencetemperature sensed by said sensing means over said time period inaccordance with the said predetermined resistance versus temperaturerelationship thereof.
 25. A method in accordance with claim 17, whereinsaid reference temperature varies with time over a relatively long timeperiod and further including the steps of immersing a temperaturesensing means in the tissue at a region sufficiently remote from theimmersed heating means so that the temperature sensed by said sensingelement is not affected by the raised temperature of said heating means,said sensing means having a predetermined resistance versus temperaturerelationship; determining the resistance of said sensing means over saidtime period; determining the reference temperature of said sensing meansover said time period; determining the desired resistance of saidheating means over said time period as a function of the resistance ofsaid sensing means and of a preselected fixed value of the resistancedifference between the resistances of said sensing means and saidheating means; maintaining the resistance of said heating means at saiddesired resistance value over said time period so that said resistancedifference remains at said preselected fixed value, the resistance ofsaid heating means varying as a function of time; determining the meantemperature of said heating means over said time period at the saiddesired resistance value of said heating means, said mean temperaturevarying as a function of time; determining the temperature differencebetween said mean temperature and said reference temperature over saidtime period, said temperature difference varying as a function of time;determining the thermal conductivity k(t) of the tissue over said timeperiod in accordance with the expression;${k(t)} = \frac{5}{\frac{\Delta \quad {T(t)}R_{h}20\quad \pi \quad \overset{\_}{a}}{V_{h}^{2}(t)} - \frac{1.0}{k_{b}}}$

where ΔT(t) is said temperature difference, R_(h)(t) is said resistanceof said heating means at said mean temperature, a is the radius of aspherical heating means having a volume equivalent to the actual volumeof said heating means, V_(h)(t) is the voltage at said heating meanswhen said power is applied and k_(b) is the predetermined thermalconductivity of said heating means.
 26. A method in accordance withclaim 25, wherein the step of determining said reference temperatureincludes the steps of immersing a temperature sensing means in thetissue at a region sufficiently remote from the immersed heating meansto that the temperature sensed by said sensing element is not affectedby the raised temperature of said heating means, said sensing meanshaving a predetermined resistance versus temperature relationship;determining over said time period the voltage at said sensing means andthe current through said sensing means; determining the referencetemperature sensed by said sensing means over said time period inaccordance with the said predetermined resistance versus temperaturerelationship thereof.
 27. A method for determining thermal properties oftissue comprising the steps of: (1) establishing a baseline criteria forthe tissue, comprising (A) determining an unperturbed temperature of thetissue; (B) causing the temperature of the tissue to change from a firstunperturbed temperature to a second temperature different from saidfirst temperature during a time period; and (C) calculating a thermalproperty value for the tissue as a function of the intrinsic thermalconductivity and a diffusivity of the tissue during a first selectedportion of said time period; (2) obtaining measurements of the tissuecomprising the steps of: (A) calculating a perfusion of the tissueduring a second selected portion of said time period using saidcalculated intrinsic thermal conductivity and diffusivity related value;(B) re-calculating the intrinsic thermal conductivity and diffusivity ofthe tissue using said calculated perfusion; (C) re-calculating theperfusion of the tissue using said recalculated intrinsic thermalconductivity and diffusivity related value; and (D) repeating steps (2B)and (2C) until the re-calculated intrinsic thermal conductivity anddiffusivity and the re-calculated perfusion each converge to asubstantially non-changing value; and (3) evaluating one or moremeasurement artifact conditions and physiological conditions todetermine if baseline conditions established by step (1) are materiallyaffected by said conditions.
 28. The method of claim 27, furthercomprising the step: (4) repeating step (1) when materially affectedbaseline conditions are indicated by step (3)
 29. A method in accordancewith claim 27, wherein step (1)(B) includes immersing a temperaturechanging means in the tissue; and activating said temperature changingmeans so as to cause said means to change the temperature of the tissue.30. A method in accordance with claim 27, wherein in step (1)(C) theintrinsic thermal conductivity and diffusivity are calculated at a firstselected portion of said first time period.
 31. A method in accordancewith claim 30, wherein in step (2)(A) the perfusion is calculated at asecond selected portion of said first time period.
 32. A method inaccordance with claim 27, wherein step (1)(B) includes immersing aheating means in the tissue; applying power to said heating means toheat the tissue from said first unperturbed temperature to said secondtemperature; and step (1)(C) includes shutting off the power to saidheating means to cause the temperature of the tissue to decay to saidfinal unperturbed temperature prior to the second selected portion ofsaid time period.
 33. A method for determining thermal properties oftissue comprising the steps of establishing baseline thermal criteriacorresponding to baseline thermal conditions of the tissue; inducing atemperature change in the tissue as a function of time; calculating atleast one selected intrinsic thermal property of the tissue using dataobtained at a first time period; calculating separately a perfusion rateof the tissue using data obtained at a second time period and said atleast one calculated intrinsic thermal property, the effects of theperfusion of the tissue at said second time period being greater thanthe effects of the perfusion of the tissue at said first time period;and determining the need for new baseline criteria for the tissue whenbaseline thermal conditions materially change.
 34. A method according toclaim 33 wherein said determining step comprises the step of evaluatingone or more physiological and artifactual conditions that may adverselyaffect the validity of the established baseline criteria
 35. A methodaccording to claim 34 wherein the artifactual conditions comprise one ormore of: ambient temperature changes, electrical interference,instrumentation drift, excessive sensor-tissue contact force that caninduce capillary collapse, insufficient sensor-tissue contact force thatcan result in artifactual transduction of perfusion, cross-talk betweensensors, and motion of the sensor relative to the tissue.
 36. A methodaccording to claim 34 wherein the physiological conditions comprise oneor more of: tissue and vascular damage, tissue edema, tissue scarformation, influence of a large vessel, change in vascular status (e.g.:blood volume, vasodilation, and vasoconstriction), changes in perfusion,changes in blood pressure, changes in tissue pressure, changes in tissuetemperature, changes in blood temperature, and changes in tissuemetabolism.
 37. A method according to any one of claims 33, 34, 35 or 36further comprising the step of automatically recalibrating baselinecriteria for one or more of the probe and the instrumentation based onthe results of said determining step.
 38. A method according to claim 33wherein said determining step comprises evaluating one or moreconditions that may adversely affect the validity at the changedtemperature of the established baseline thermal criteria.
 39. A methodfor determining the perfusion in live tissue with automaticrecalibration comprising the steps: 1) measuring the temperature of thetissue at a selected location; 2) determining if the temperature at theselected location is stable, wherein if the temperature is not stablethen repeating step 1; 3) raising the temperature of the tissue at theselected location a predetermined amount; 4) measuring the powerprovided in step (3) to maintain the raised temperature; 5) measuringthe temperature at the selected location and calculating the perfusion;6) repeating step 5 for a period of time; 7) determining if thetemperature of the tissue at the selected location is stable, wherein ifthe temperature is not stable, then repeating step 1; 8) determining ifa function of the power measured in step (4) is less than an establishedmaximum value, wherein if not less than the established maximum, thenrepeating step 1; 9) determining if the total time the measurements havebeen taken over is less than an established maximum, wherein if thetotal is not less than the established maximum, then repeating step 1;10) repeating step
 5. 40. A method for determining thermal properties oftissue with automatic recalibration comprising the steps: 1) providingan apparatus for determining properties of tissue, comprising: acomputer, a display in electrical communication with the computer, adetector circuit in electrical communication with the computer, a powersupply in electrical communication with the computer, display anddetector circuit; a keypad in electrical communication with the detectorcircuit, and a probe in electrical communication with the detectorcircuit; 2) inserting the probe into the tissue; 3 having/operating thedevice perform the following steps: A) measuring the temperature of thetissue at a selected location; B) determining if the temperature at theselected location is stable, wherein if the temperature is not stablethen repeating step 1; C) raising the temperature of the tissue at theselected location a predetermined amount; D) measuring the temperatureat the selected location and calculating the perfusion; E) repeatingstep D for a set period of time; F) determining if the temperature ofthe tissue at the selected location is stable, wherein if thetemperature is not stable, then repeating step 1; G) determining if therate of perfusion is less than an established maximum value, wherein ifrate of perfusion is not less than the established maximum, thenrepeating step A; H) determining if the total time the measurements havebeen taken over is less than an established maximum, wherein if thetotal is not less than the established maximum, then repeating step A;I) repeating step D.
 41. A method comprising the steps: 1) measuring T1and T2; 2) determining if T1 and T2 are stable; 3) if T1 and T2 are notstable, then repeating step 1; 4) if T1 and T2 are stable, then settingT2 to T2+DT; 5) measuring TI and calculating P2; 6) determining if P2data has been acquired for a selected time period; 7) if 10 seconds ofP2 data not acquired, then repeat step 5; 8) if 10 seconds of P2 datahas been acquired, then calculating K_(m); 9) calculating w; 10)determining if T1 is stable; 11) if T1 is not stable, then repeatingstep 1; 12) if T1 is stable, then determining if dP2/dt is less thandP/dt(max); 13) if dP2/dt is not less than dP/dt(max), then repeatingstep 1; 14) if dP2/dt is less than dP/dt(max), then determining if t isless than t(max); 15) if t is not less than t(max), then repeating step1; 16) if t is less than t(max), then repeating step
 5. 42. A method fordetermining thermal properties of tissue comprising the steps of: (1)establishing baseline criteria corresponding to the baseline thermalconditions of the tissue, comprising: contacting the tissue with aheating means having a predetermined resistance versus temperaturerelationship; and determining a reference temperature for the tissuewhen the tissue is unheated; (2) obtaining measurements of the tissuecomprising the steps of: applying power to said heating meanssufficiently rapidly to heat said heating means to a temperature abovesaid reference temperature so that the power necessary to maintain saidtemperature varies as a function of time; determining the time varyingrelationship between the power required to maintain said heating meansat said temperature after said temperature has been reached and the timeduring which said power is being applied thereto; determining thetemperature difference between said heating means temperature and saidreference temperature and determining the resistance of said heatingmeans at said temperature; determining the thermal conductivity of thetissue as a function of said temperature difference, of the resistanceof said heating means at said temperature, and of said applied power inaccordance with said time varying power and time relationship; and (3)evaluating one or more physiological and measurement artifact conditionsto determine if baseline criteria established in step (1) are materiallyaffected thereby and if so (4) repeating step (1).
 43. A method fordetermining thermal properties of tissue comprising the steps of: (1)establishing baseline criteria corresponding to the baseline thermalconditions of the tissue, comprising: determining the thermalconductivity of a heating means as a function of temperature; contactingthe tissue with said heating means; and determining a referencetemperature of the tissue when the tissue is unheated; (2) obtainingmeasurements of tissue comprising the steps of: applying power to saidheating means sufficiently rapidly to heat said heating means to atemperature above said reference temperature so that the power necessaryto maintain said temperature varies as a function of time; determiningthe time varying power and time relationship between the power requiredto maintain said temperature and the time during which said power isapplied to said heating means; determining the temperature differencebetween said temperature and said reference temperature; determining thethermal conductivity of the tissue as a function of said temperaturedifference, and of said applied power in accordance with said timevarying power and time relationship; and (3) evaluating one or morephysiological and measurement artifact conditions to determine ifbaseline criteria established in step (1) are materially affectedthereby and if so (4) repeating step (1).
 44. A system for monitoringperfusion in living tissue comprising: a sensor adapted for thermalcontact with tissue at a selected location; means for determining systembaseline criteria corresponding to baseline thermal conditions of thetissue; a heater for changing the temperature of tissue at saidlocation; means for determining a perfusion related value for tissue atsaid location as a function of data from said sensor and the output ofsaid heater; and means for evaluating one or more conditions that mayaffect system baseline criteria and assessing the validity at thechanged temperature of the system baseline criteria.
 45. A systemaccording to claim 44 wherein said evaluating means evaluates conditionsselected from one or more physiological conditions and artifactualconditions that may change to affect system baseline criteria as a basisfor assessing the validity of the system baseline criteria.
 46. A systemaccording to claim 45 wherein said calibrating means evaluates one ormore conditions selected from artifactual probe and instrumentconditions.
 47. A system according to claim 45 wherein the artifactualconditions evaluated comprise one or more of: ambient temperaturechanges, electrical interference, instrumentation drift, excessivesensor-tissue contact force that can induce capillary collapse,insufficient sensor-tissue contact force that can result in artifactualtransduction of perfusion, cross-talk between sensors, and motion of thesensor relative to the tissue.
 48. A system according to claim 45wherein the physiological conditions evaluated comprise one or more of:tissue and vascular damage, tissue edema, tissue scar formation,influence of a large vessel, change in vascular status (e.g.: bloodvolume, vasodilation, and vasoconstriction), changes in perfusion,changes in blood pressure, changes in tissue pressure, changes in tissuetemperature, changes in blood temperature, and changes in tissuemetabolism.
 49. A system according to any one of claims 44, 45, 46, 47or 48 further comprising means for indicating a need for new systembaseline criteria in response to the assessment of said evaluatingmeans.
 50. A system according to any one of claims 44, 45, 46, 47 or 48further comprising means for automatically recalibrating system baselinecriteria for one or more of the probe and the instrumentation based onthe evaluation of said evaluating means.
 51. Apparatus for determiningthe perfusion of blood in living tissue comprising: means in thermalcontact with the tissue for sensing the reference temperature of thetissue when the tissue is unheated; means in thermal contact with thetissue for heating the tissue; means for applying power to said heatingmeans sufficiently rapidly to raise the temperature of said heatingmeans to a temperature above said reference temperature so that thepower necessary to maintain said heating means temperature varies as afunction of time; data processing means for determining the temperaturedifference between said heating means temperature and said referencetemperature, for determining the resistance of said heating means atsaid heating means temperature and for determining the time varyingrelationship between the power required to maintain said heating meansat said heating means temperature after said temperature has beenreached and the time during which said power is being applied thereto;said data processing means further being responsive to said temperaturedifference, said heating means resistance and said time varying powerand time relationship for determining a perfusion related value; meansfor evaluating conditions that affect the reference temperature of thetissue and recognizing conditions under which the reference temperatureis no longer valid; and means for providing an output in response tosaid evaluating and recognizing means.
 52. Apparatus according to claim51 further comprising means for automatically calibrating said sensingmeans in response to said output.
 53. Apparatus according to claim 51wherein said recognizing means comprises means for recognizing one ormore physiological and artifactual conditions.
 54. Apparatus accordingto claim 53 wherein the artifactual conditions comprise one or more of:ambient temperature changes, electrical interference, instrumentationdrift, excessive sensor-tissue contact force that can induce capillarycollapse, insufficient sensor-tissue contact force that can result inartifactual transduction of perfusion, cross-talk between sensors, andmotion of the sensor relative to the tissue.
 55. A system according toclaim 53 wherein the physiological conditions comprise one or more of:tissue and vascular damage, tissue edema, tissue scar formation,influence of a large vessel, change in vascular status (e.g.: bloodvolume, vasodilation, and vasoconstriction), changes in perfusion,changes in blood pressure, changes in tissue pressure, changes in tissuetemperature, changes in blood temperature, and changes in tissuemetabolism.
 56. Apparatus for determining thermal properties of livingtissue comprising: means adapted to contact tissue for sensing areference temperature of the tissue when the tissue is unheated; meansfor heating tissue including tissue contacted by said heating means,said heating means having a predetermined thermal conductivity and apredetermined thermal diffusivity; means for applying power to saidheating means sufficiently rapidly to raise the temperature of saidheating means above said reference temperature so that the powernecessary to maintain said heating means temperature varies as afunction of time; data processing means for determining the temperaturedifference between said heating means temperature and said referencetemperature, for determining the resistance of said heating means atsaid heating means temperature and for determining the time varyingrelationship between the power required to maintain said heating meansat said temperature after said temperature has been reached and the timeduring which said power is being applied thereto; said data processingmeans further being responsive to said temperature difference, saidheating means resistance, said applied power in accordance with saidtime varying power and time relationship, said predetermined thermalconductivity of said heating means, and a change in said referencetemperature for determining the thermal conductivity of the tissue. 57.Apparatus in accordance with claim 56, wherein said sensing means andsaid heating means comprises a single element capable of sensing thetemperature of the tissue and of heating the tissue.
 58. Apparatus inaccordance with claim 57 wherein said single element is a thermistorbead element.
 59. Apparatus in accordance with claim 57, and furtherincluding means for maintaining said heating means temperature at afixed, predetermined value above said reference temperature, saidreference temperature being determined and said heating meanstemperature being maintained over a relatively short time intervalduring which said reference temperature remains substantially constantwhereby said temperature difference and the resistance of said heatingmeans also remain substantially constant.
 60. Apparatus in accordancewith claim 56, wherein said heating means and said sensing meanscomprise respectively a first heating element adapted to be immersed ata first region of the tissue; and a second element adapted to beimmersed at a second region of the tissue sufficiently remote from saidfirst region as to be not materially affected by the heating of saidfirst element.
 61. Apparatus in accordance with claim 60 wherein saidfirst and second elements are thermistor bead elements.
 62. Apparatus inaccordance with claim 60, for use over a relatively long time periodduring which said reference temperature varies with time and whereinsaid second element determines said reference temperature over said timeperiod; and further including means for maintaining said first elementtemperature and the resistance of said first element at said firstelement temperature at fixed predetermined values over said time periodduring which said reference temperature varies whereby the temperaturedifference there between varies over said time period.
 63. Apparatus inaccordance with claim 60, for use over a relatively long time periodduring which said reference temperature varies with time wherein saidsecond element determines said reference temperature over said timeperiod; and further including means for determining the first elementtemperature over said time period as a function of said referencetemperature and a preselected fixed value of said temperaturedifference; means for maintaining the resistance of said first elementover said time period at a value such as to maintain the temperaturedifference between said first element temperature and said referencetemperature at said preselected fixed value, said resistance varying asa function of time; and means for determining the thermal conductivityof the tissue over said time period as a function of said temperaturedifference, said resistance of said first element, the power applied toheat said first element and said thermal conductivity of said firstelement.
 64. Apparatus in accordance with claim 63, wherein said dataprocessing system includes means for determining the intrinsic thermalconductivity k_(m) of the tissue when no fluid is flowing therein; meansfor determining the effective thermal conductivity k_(eff)(t) of thetissue when a fluid having a predetermined heat capacity is flowingtherein; means for determining the ratio of k_(eff)(t)/k_(m) over saidtime period; and means for determining the rate of flow ω(t) of saidfluid in the tissue as a function of said ratio.
 65. Apparatus inaccordance with claim 60, for use over a relatively long time periodduring which said reference temperature varies with time wherein saidsecond element determines said reference temperature over said timeperiod; and further including means for determining the resistance ofsaid second element over said time period; means for determining thedesired resistance of said first element over said time period as afunction of the resistance of said second element and of a preselectedfixed value of the resistance difference between the resistances of saidsecond and said first elements; means for maintaining the resistance ofsaid first element at said desired resistance so that said resistancedifference is maintained at said predetermined fixed value, theresistance of said second element varying as a function of time; meansfor determining the temperature of said first element over said timeperiod at said desired resistance of said first element, saidtemperature varying as a function of time; means for determining thetemperature difference between said first element temperature and saidreference temperature over said time period, said temperature differencevarying as a function of time; means for determining the thermalconductivity of the tissue over said time period as a function of saidtemperature difference, said resistance of said first element, the powerapplied to heat said first element and the conductivity of said firstelement.
 66. Apparatus in accordance with claim 65, wherein said dataprocessing system includes means for determining the intrinsic thermalconductivity k_(m) of the tissue when no fluid is flowing therein; meansfor determining the effective thermal conductivity k_(eff)(t) of thetissue when a fluid having a predetermined heat capacity is flowingtherein; means for determining the ratio of k_(eff)(t)/k_(m) over saidtime period; and means for determining the rate of flow ω(t) of saidfluid as a function of said ratio.
 67. An apparatus for determiningthermal properties of living tissue, comprising: a computer; a displayin electrical communication with the computer; a detector circuit inelectrical communication with the computer; a power supply in electricalcommunication with the detector circuit; a keypad in electricalcommunication with the detector circuit; and a probe in electricalcommunication with the detector circuit.
 68. The apparatus of claim 67,further comprising an external serial port in electrical communicationwith the detector circuit.
 69. The apparatus of claim 67, furthercomprising an external output, selected from the formats of analogand/or digital.
 70. The apparatus of claim 67, wherein the computer is asingle board computer.
 71. The apparatus of claim 67, wherein thecomputer comprises a first and second serial port.
 72. The apparatus ofclaim 67, wherein the display is a flat panel display.
 73. The apparatusof claim 67, wherein the first power supply is an isolated power supply.74. The apparatus of claim 67, wherein the second power supply is anun-isolated power supply.
 75. The apparatus of claim 67, wherein thedetector circuit comprises: an isolated component comprising: aprocessor, a control circuit in electrical communication with theprocessor, and at least one analog to digital converter.
 76. A methodfor determining perfusion in living tissue comprising the steps of: (1)establishing baseline criteria, comprising (A) determining anunperturbed temperature of the tissue; (B) causing the temperature ofthe tissue to change from a first unperturbed temperature to a secondtemperature different from said first temperature for a time period, and(C) determining a value or values for one or more thermal properties oftissue during said time period; (2) calculating a perfusion value forthe tissue during said time period using said thermal property value orvalues, and (3) evaluating one or more physiological and artifactualconditions to determine if baseline criteria established by step (1) arematerially affected by said conditions and if so repeating step (1). 77.A method according to claim 76 wherein said thermal properties includeone or both of thermal conductivity and thermal diffusivity.